Bicyclic pyrimidines

ABSTRACT

Novel bicyclic pyrimidine compounds for use as drugs and having formula (I). Said novel compounds and physiologically tolerable salts thereof may be used in therapeutics, particularly for suppressing tumour cell resistance to antineoplastic agents. ##STR1##

This is a section 371 of PCT/FR93/01211, filed Dec. 9, 1993.

TECHNICAL FIELD

The present invention relates to new bicyclic pyrimidine compounds, aprocess for their preparation, and pharmaceutical compositionscontaining them.

PRIOR ART

The prior art in the pharmaceutical field is illustrated especially bypublished European Patent Applications Nos. 0.495 982 A₁ and 0 514 540A₁, which relate to the compounds of formulae: ##STR2## respectively,which formulae essentially differ from the compounds of the presentinvention in the meaning of the substituents --Y'--Z' and Y"--Z" on thepyrimidine nucleus, and in their pharmacological activity--the saidproducts of the prior art being active against hypoxaemia associatedwith respiratory disorders whilst the compounds of the present inventionpartially or completely reverse the resistance of tumour cells toanti-cancer agents.

STATEMENT OF THE INVENTION

The invention relates especially to bicyclic pyrimidine compounds offormula I: ##STR3## wherein: T and U, which are the same or different,each represents a --CH-- radical or a nitrogen atom so as to form withthe pyrimidinyl group a heterocycle selected from: purine,pyrazolo[3,4-d]pyrimidine, pyrrolo[2,3-d]pyrimidine and1,2,3-triazolo[4,5-d]pyrimidine;

R and R', which are the same or different, each represents an alkylradical having from 1 to 5 carbon atoms or an alkenyl radical havingfrom 2 to 5 carbon atoms, each in straight or branched chain;

A represents a heteromonocyclic radical of formula: ##STR4## wherein: Brepresents a radical of formula: ##STR5## wherein R" is a hydrogen atomor an alkyl radical having from 1 to 5 carbon atoms in straight orbranched chain and

t represents an integer of from 1 to 3;

p is zero or one;

X and Y, which are the same or different, each represents a hydrogenatom, a halogen atom, or an alkyl or alkoxy radical each having from 1to 5 carbon atoms in straight or branched chain;

m and n, which are the same or different, each represents an integer offrom 1 to 3;

R₁ and R₂, which are the same or different, each represents a hydrogenatom or an alkyl radical having from 1 to 5 carbon atoms in straight orbranched chain, or together represent a single bond, an oxygen orsulphur atom, a radical --(CH₂)_(r) -- in which r represents an integerof from 1 to 3, a radical --CH═CH--, --O--CH₂ --, --S--CH₂ --, --SO₂--CH₂ --, --CO--CH₂ --, ##STR6## in each of which R'" represents ahydrogen atom or an alkyl radical having from 1 to 5 carbon atoms instraight or branched chain, or

R₁ and R₂ together represent the radical ##STR7## in which the terminalCH₂ is attached to the closest carbon of the adjoining benzene ring sothat the whole: ##STR8## forms the tetracyclic radical of formula:##STR9## R₃ represents a hydrogen atom or a phenyl radical; and also tothe chiral compounds and their enantiomers.

The present invention relates also to a process for the preparation ofthe compounds of formula I which is characterised in that:

a chlorinated compound of formula II: ##STR10## wherein T, U and R' areas defined above, is condensed with the amine of formula: ##STR11##whichever it is desired to attach in the 6-position, (R, X, Y, m, n, R₁,R₂, R₃, p and A in those formulae being as defined above),

then the product so obtained which, depending on the case concerned, isof formula: ##STR12## is condensed with the other amine of formula IIIor IV which it is desired to attach in the 2-position--the order ofreactivity of the amines with the dichlorinated compounds II being known[cf. Heterocyclic compounds Part II, Ed. D. J. Brown, Wiley-Interscience(1971), Chapter V, p. 160].

Those successive condensations are carried out especially advantageouslyas follows:

The reaction of compound II with the amine it is desired to attach inthe 6-position is carried out in a polar solvent, such as, for example,an alcohol containing from 2 to 5 carbon atoms, dimethylformamide ordimethylacetamide, at a temperature of approximately 60° C., in thepresence of an acceptor for the hydracid formed during the course of thereaction; that acceptor may be, for example, triethylamine or an excessof the amine used in the reaction.

The condensation product thus obtained is then condensed with the otheramine (to be attached in the 2-position) in a polar solvent of the sametype as that used for the preceding condensation, the condensation beingcarried out in an autoclave at a temperature of from 130° to 150° C. inthe presence of an acceptor for the hydracid formed during the course ofthe reaction; that acceptor may be, for example, triethylamine or anexcess of the amine used in the reaction.

The starting materials of formula II were prepared from knowndichlorinated compounds, such as:

2,4-dichloropyrrolo[2,3-d]pyrimidine (cf. ROBINS R. K. et al., JACS(1984) 106, 6379);

5,7-dichlorotriazolo[4,5-d]pyrimidine (cf. BITTERLI P., ERLENMEYER H.,Helv. Chem. Acta (1951) 34, 835), and

4,6-dichloropyrazolo[3,4-d]pyrimidine (cf. ROBINS R. K., JACS (1957) 79,6407).

Those dichlorinated compounds, which correspond to the formula:##STR13## are then reacted with an alcohol of formula:

    R'-OH

in which R' is as defined hereinbefore, according to the Mitsunobumethod--Synthesis (1981), 1, by analogy with M. IWAKAWA et al, Can. J.Chem. (1978) 56, 326, and TOYOTA A. et al, Chem. Pharm. Bull. (1992),40, 1039--to yield the starting materials of formula II.

In certain cases, substitution isomers may be obtained, which may beseparated by chromatography.

The compounds of formula I may be converted into addition salts withacids, which salts, as such, form part of the present invention. Theremay be mentioned as acids that can be used for the formation of thosesalts, for example, in the inorganic series hydrochloric, hydrobromic,sulphuric, nitric and phosphoric acid and, in the organic series,acetic, propionic, maleic, fumaric, tartaric, oxalic, benzoic,methanesulphonic and isethionic acid.

The compounds of formula I may be purified by physical methods, such asrecrystallisation of the bases or salts, chromatography (especiallyflash chromatography on silica 35-70 μ eluted with ethyl acetate or thesystem CH₂ Cl₂ /methanol or CH₂ Cl₂ /acetone), or by chemical methods,such as the formation of addition salts with acids and decomposition ofthose salts with alkaline agents.

The compounds of formula I and their physiologically tolerable additionsalts have valuable pharmacological and therapeutic properties, and inparticular they partially or completely reverse the resistance of tumourcells to anti-cancer agents, which allows them to be used as adjuvantsin the treatment of cancers with the aim of reducing or suppressing theresistance of the tumour cells to the anti-cancer agents.

The present invention relates also to pharmaceutical compositionscomprising as active ingredient a compound of formula I or aphysiologically tolerable salt thereof, mixed with or in associationwith an appropriate pharmaceutical excipient.

The so-obtained pharmaceutical compositions are generally presented indosage form and may comprise from 0.1 to 1000 mg of active ingredient.They may be, for example, in the form of tablets, dragees, gelatincapsules, suppositories or injectable or drinkable solutions, and may beadministered by the oral, rectal or parenteral route.

The dosage varies, especially in accordance with the age and weight ofthe patient, the route of administration, the nature of the disorder andassociated treatments, and ranges from 0.1 to 1000 mg of activeingredient per administration.

The following Examples illustrate the invention. The melting points aredetermined using a capillary tube (cap) or a Kofler hot plate (K).

Example 1

9-allyl-6-allylamino-2-{4-[(10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5-yl)methylamino]piperidino}purine##STR14## 0.75 ml of allylamine is added to a solution of 1.15 g of2,6-dichloro-9-allylpurine in 15 ml of ethanol and the mixture isstirred for 1 hour at room temperature and then heated at 50° C. for 30minutes. After evaporation of the solvent, the mixture is taken up inCH₂ Cl₂ -H₂ O, decanted, and the solvent is evaporated. The residue isrecrystallised from ethanol. 1 g of 2-chloro-6-allylamino-9-allylpurine,melting at 110°-112° C. is obtained. 0.85 g of that compound isdissolved in 20 ml to butanol, 1.04 g of4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]-piperidine(oil), 0.5 g of K₂ CO₃ and 0.1 g of potassium iodide are added to thesolution obtained, and the mixture is heated at reflux for 10 hours. Thereaction mixture is then concentrated and the residue is taken up in CH₂Cl₂ -H.sub. 2 O. The mixture is decanted, the organic phase is thenevaporated, and the residue is chromatographed using ethyl acetate aseluant. 0.6 g of9-allyl-6-allylamino-2-{4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]piperidino}-purine is isolated in the form of crystalsmelting (cap) at 142°-144° C. The 9-allyl-2,6-dichloropurine used asstarting material was prepared by reacting allyl alcohol and2,6-dichloropurine in tetrahydrofuran according to the Mitsunobu method.The amine used as starting material was prepared by debenzylation of thecorresponding piperidine melting at 78°-81° C., which was itselfprepared by reductive alkylation with NaBH₃ CN, in methanol, of amixture of 1-benzylpiperidone and(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamine hydrochloridemelting (cap) at 275°-280° C.

Example 2

9-allyl-2-allylamino-6-{4-[(10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5-yl)methylamino]piperidino}purine##STR15##

3 g of4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]piperidineare added to a solution of 1.15 g of 9-allyl-2,6-dichloropurine in 20 mlof ethanol and the mixture is stirred for 3 hours at room temperatureand then for 30 minutes at 50° C. The mixture is then treated asdescribed in Example 1. The residue obtained is recrystallised fromether. 1.8 g of white crystals melting (cap) at 146°-148° C. areobtained. By proceeding as in Example 1, starting from 1.8 g of the2-chloropurine compound so obtained dissolved in 20 ml of butanol andheated to 150° C. in the presence of 0.6 ml of allylamine, 0.7 g of9-allyl-2-allylamino-6-{4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]piperidino}purineis obtained in the form of a resinous product of which the difumarate,recrystallised from ethanol, melts (cap) at 191°-194° C.

Examples 3 to 28

The following compounds were prepared by applying the method describedin the above Examples:

3)9-allyl-6-allylamino-2-{4-[2,2-bis(4-fluorophenyl)-ethylamino]piperidino}purine,m.p. (cap): 143°-145° C.

4)9-allyl-2-allylamino-6-{4-[2,2-bis(4-fluorophenyl)-ethylamino]piperidino}purine,m-p. (cap) of the corresponding dimaleate: 151°-152° C.

5)9-allyl-6-allylamino-2-{4-[(6,11-dihydrodibenzo[b,e]-oxepin-11-yl)methylamino]piperidino}purine,m.p. (K) of the corresponding fumarate: 240° C.

6)9-allyl-6-allylamino-2-{4-[(5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]piperidino}purine,m.p. (K) of the corresponding fumarate: 250° C.

7)6-allylamino-2-{4-[(10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)methylamino]piperidino}-9-propylpurine,m.p. (K) of the corresponding fumarate: 237° C.

8)9-allyl-2-{4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]piperidino}-6-propylaminopurine,m.p. (K) of the corresponding fumarate: 213° C.

9) 1-allyl-4-allylamino-6-{4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]piperidino}pyrazolo[3,4-d]pyrimidine,m.p. (cap) of the corresponding fumarate: >230° C. with decomposition.

10)7-allyl-4-allylamino-2-{4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]piperidino}pyrrolo[2,3-d]pyrimidine,m.p. (cap) of the corresponding fumarate: 160°-163° C.

11)3-allyl-7-allylamino-5-{4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]piperidino}1,2,3triazolo[4,5-d]pyrimidine,m.p. (cap) of the corresponding fumarate: 159°-162° C.

12)9-allyl-6-allylamino-2-{4-[(2,2-diphenylethyl)amino]piperidino}purine,m.p. (K): 150° C.

13)9-allyl-6-allylamino-2-{4-[(3-chloro-6-methyl-5,5-dioxo-6,11-dihydrodibenzo)[c,f][1,2]thiazepin-11-yl)methylamino]piperidino}purine,m.p. (K) of the corresponding fumarate: 174° C.

14)9-allyl-6-allylamino-2-{4-[(2-methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]piperidino}purine,m.p. (K) of the corresponding fumarate: 205° C.

15) (+)--(R)-- or--(S)-9-allyl-6-allylamino-2-{4-[(3-chloro-6-methyl-5,5-dioxo-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-yl)amino]piperidino)purine,m.p. (K) of the corresponding dihydrochloride: 174° C.

16) (-)--(R)-- or--(S)-9-allyl-6-allylamino-2-{4-[(3-chloro-6-methyl-5,5-dioxo-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-yl)amino]piperidino}purine,m.p. (K) of the corresponding dihydrochloride: 210° C.

17)9-allyl-2-allylamino-6-{4-[(3-chloro-6-methyl-5,5-dioxo-6,11-dihydrodibenzo[c,f][1,2]thiazepin-ll-yl)methylamino]piperidino}purine,m.p. (K) of the corresponding dihydrochloride: 210° C.

18)9-allyl-2-allylamino-6-{4-[(6,11-dihydrodibenzo[b,e]oxepin-11-yl)methylamino]piperidino}purine,m.p. (K) of the corresponding difumarate: 186° C.

19)9-allyl-2-allylamino-6-{4-[(2-methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-yl)methylamino]piperidino}purine,m.p. (K) of the corresponding difumarate: 188° C.

20)9-allyl-2-allylamino-6-{4-[(5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]piperidino)purine,m.p. (K) of the corresponding difumarate: 200° C.

21)9-allyl-6-allylamino-2-{4-[(11-methyl-10,10-dioxo-5,11-dihydro-10-thia-11-azadibenzo[a,d]cyclohepten-5yl)amino]piperidino}purine,m.p. (K): 182° C.

22)9-allyl-6-allylamino-2-{4-[(10,10-dioxo-11-propyl-5,11-dihydro-10-thia-11-azadibenzo[a,d]cyclohepten-5yl)methylamino]piperidino}purine,m.p. (K): 165° C.

23)9-allyl-6-allylamino-2-{4-[(2,3,4-trimethoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]piperidino}purine,m.p. (K) of the corresponding fumarate: 170° C.

24)9-allyl-6-allylamino-2-{4-[(6,11-dihydrodibenzo[b,e]oxepin-11-yl)amino]piperidino}purine,m.p. (K) of the corresponding fumarate: 223° C.

25)9-allyl-6-allylamino-2-{4-[(5,11-dihydro-6-oxodibenzo[b,e]azepin-11-yl)methylamino]piperidino}purine,m.p. (K) of the corresponding fumarate: 240° C.

26)9-allyl-6-allylamino-2-{4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)amino]piperidino}purine,m.p. (K): 114° C.

27)9-allyl-2-allylamino-6-{4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)amino]piperidino)purine,m.p. (K) of the corresponding fumarate: 170° C.

28)9-allyl-6-allylamino-2-{4-[(2,2,2-triphenylethyl)amino]piperidino}purine,m-p. (K): 175° C.

Example 29: PHARMACOLOGICAL STUDY

Resistance to anti-cancer agents is a major obstacle to theeffectiveness of anti-tumour drugs. Of the different types ofresistance, "Multidrug Resistance" (MDR) is particularly interesting,since it is induced by compounds of natural origin that are activeagainst solid tumours (anthracyclines, vinca alkaloids,epipodophyllotoxins for example) and is very frequent in certain cancers(colon, for example). When tumour cells are exposed in vitro or in vivoto one of those drugs they become resistant, to varying degrees, to allof those compounds. The resistance phenomenon is as a result of theaction of an inducible membrane protein, P-gP 170, the role of which isto increase the efflux of the cytotoxic agent, thus reducing itsintracellular concentration, which results in the loss of sensitivity ofthose cells to the drug. Some medicaments, used in other pathologies,are known to reverse that resistance partially or completely (Tsuruo T.,Mechanisms of multidrug resistance and implications for therapy. int. J.Cancer Res., 79, 285-296, 1988; Rothenberg, M. and Ling V., Multidrugresistance: molecular biology and clinical relevance, J.N.C.I., 81,907-910, 1989; Gottesman M. M. and Pastan, I., Resistance to multiplechemotherapeutic agents in human cancer cells, Trends Pharmacol. Sci.,9, 54-58, 1989; Endicott J. A. and Ling V., The biochemistry ofP-glycoprotein-mediated multidrug resistance, Annu. Rev. Biochem.,58,137-171, 1989). When the modulating agent is added at the same timeas the cytotoxic agent, it reduces or completely suppresses. MDR-typeresistance. Certain medicaments, such as verapamil, amiodarone orcyclosporin, have been used clinically to overcome that resistance, buttheir intrinsic pharmacological properties and their toxicity limittheir use considerably. This gives rise to the interest in searching forcompounds that reverse the MDR phenotype but that do not have otherpharmacological properties and that are non-toxic. The pharmacologicalstudy of the compounds of the present invention consisted first of allin an evaluation in vitro carried out on resistant cells. The parametermeasured is the cytotoxicity of the anti-tumour drug, quantified in theabsence and in the presence of the reversing compound. Also measured wasthe effect of the compounds on the intracellular concentration of thecytotoxic agent. In effect, the known compounds for reversing MDR act byincreasing the intracellular concentration of cytotoxic agent. Thiseffect is the consequence of inhibiting the action of P-gP 170 which isresponsible for the efflux of the drug. This study was completed by anin vivo study, using a murine leukaemia resistant to vincristine(P388/VCR) and using the compounds in association with vincristine.

Material and methods:

1) Activity in vitro

Cytotoxicity

Two resistant cell lines were used:

a Chinese hamster lung line, DC-3F/AD, the resistance of which wasinduced by actinomycin D. Its resistance factor is greater than 10,000,and it is thus an extremely resistant line.

and a human line from an epidermoid carcinoma of the mouth, KB-A1, theresistance of which was induced by adriamycin (ADR). Its resistancefactor is approximately 300.

These two lines are also resistant to vinca alkaloids (vincristine andvinblastine). The cells are cultivated in a complete culture medium(RPMI 1640), containing 10 % foetal calf serum, 2 mM glutamine; 50units/ml penicillin, 50 μg/ml streptomycin, 10 mM Hepes. The cells aredistributed on microplates and exposed to the cytotoxic compound(actinomycin D or adriamycin) at 9 concentrations (2 by 2 seriesdilutions). The compounds tested for their capacity to reverse MDR areadded at the same time as the cytotoxic agent. The cells are thenincubated for 4 days. The number of viable cells is then quantified by acolorimetric assay, the Microculture Tetrazolium Assay (Carmichael J.,DeGraff W. G., Gazdar A. F., Minna J. D. and Mitchell J. R. Evaluationof a tetrazolium-based semiautomated colorimetric assay: assessment ofchemosensitivity testing, Cancer Res., 47, 936-942, 1987). The resultsare expressed as IC₅₀, the concentration of cytotoxic agent thatinhibits the proliferation of the treated cells by 50% compared with thecontrol. The results are expressed as a reversion factor (RF): ##EQU1##

Flow cytometry

Certain anti-cancer compounds such as adriamycin (ADR) exhibit theproperty of being fluorescent after excitation by a light source ofknown wavelength. By measuring that fluorescence, it is thus possible toobtain a relative measurement of the intracellular concentration of ADR.Flow cytometry (FCM) is a preferred method of carrying out this kind ofmeasurement and thus determining quickly if certain active compounds actby increasing the intracellular concentration of ADR. The resistant cellline used is KB-A1. The cells (500×10³ per ml) were exposedsimultaneously to ADR at a fixed concentration (50 μM) and to the testedcompounds at various concentrations. After 5 hours' incubation, theintracellular accumulation of ADR was evaluated by FCM. The analyseswere carried out on a flow cytometer ATC3000 (BRUKER-FRANCE) fitted witha 2025 argon laser (SPECTRA-PHISICS-FRANCE) optimised at 488 nm for acapacity of 600 mW. The analysis of each of the samples was carried outon a total of 10,000 cells at a rate of 1,000 cells per second. Theresults were presented in the form of linear histograms of theintracellular ADR fluorescence.

Expression of the results: for each of the histograms the meanfluorescence per channel (MEAN) was determined by the information systemof the apparatus. For all experiments:

a negative control (cells without ADR) fixed the autofluorescencethreshold.

a positive control (cells with ADR) determined the MEAN value=MN1.

the "test" tubes (cells with ADR and with compound) were used todetermine, for each of the compounds and at each of the concentrations,the MEAN values=MN2.

The results are expressed in the form of variations from the meanfluorescence obtained for each of the "test" tubes (MN2) in relation tothe mean fluorescence obtained with the positive control (MN1):VAR-MEAN=MN2-MN1. The parameter expressed is thus the increase in ADRfluorescence in the presence of the tested compounds

2) Activity in vivo

Anti-tumour activity

The sensitive parent line P388 (murine leukaemia) and the sub-lineresistant to vincristine, P388/VCR, were supplied by NCI (Frederick,USA). The tumour cells (10⁶ cells) were inoculated on day 0 into theintraperitoneal cavity of female B6D2F1 mice (Iffa Credo, France)weighing from 18 to 20 g (groups of 8 to 10 animals). In the case ofi.p. administration of the compounds to be tested, the animals receivedon days 1, 5 and 9:

administration by the i.p. route of 25, 50 or 75 mg/kg of the compoundof the present invention to be tested, then

30 to 60 minutes later, an administration by the i.p. route of 0.50mg/kg of vincristine (used as a reference anti-tumour agent).

In the case of p.o. administration of the compounds to be tested, theanimals received on days 1, 2, 3 and 4:

an administration by the oral route of 100 mg/kg of the compound of thepresent invention to be tested, then

30 to 60 minutes later, an administration by the i.p. route of 0.25mg/kg of vincristine.

The anti-tumour activity is expressed as follows: ##EQU2##

The activity of the reversing compound is expressed as T/V: ##EQU3##

Results

1) Activity in vitro

Table 1 gives the reversion factor values obtained with the variouscompounds with the line DC-3F/AD and also the increase in the ADRfluorescence (VAR-MEAN) obtained with the various compounds with theline KB-A1. The compounds are far more active than the referencecompounds.

Table 2 shows the reversion factor values obtained with the variouscompounds with the line KB-A1. The compounds of the invention are veryactive, some of them even far more active than the reference compounds,and completely reverse the resistance of KB-A1 (human cancer line) toadriamycin.

2) Activity in vivo

Table 3 shows the increase in anti-tumour activity of vincristine invivo obtained with two representative compounds of the presentinvention. The compounds of Examples 1 and 2 of the inventionadministered i.p. substantially increase the anti-tumour activity ofvincristine against a resistant tumour, vincristine thus exhibiting thesame activity as against a sensitive tumour.

Table 4 shows the anti-tumour activity of the compounds of the presentinvention, administered p.o., on the line P388/VCR.

The compounds of the invention are very active even when administered bythe oral route. The most active compounds totally restore theanti-tumour activity of vincristine.

ACTIVITY IN VITRO

                  TABLE 1                                                         ______________________________________                                                                INTRACELLULAR                                                                 ACCUMULATION OF                                                  REVERSION    ADRIAMYCIN                                                       FACTOR 5 μM                                                                             VAR-MEAN at 5 μM                                   COMPOUNDS  DC-3F/AD     KB-A1                                                 ______________________________________                                        REFERENCE                                                                     COMPOUNDS                                                                     verapamil     3          13                                                   cyclosporin A                                                                               4          23                                                   COMPOUNDS                                                                     OF THE                                                                        EXAMPLES                                                                      1          5173         110                                                   2          3368         111                                                   ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        COMPOUNDS  REVERSION FACTOR 5 μM KB-A1                                     ______________________________________                                        REFERENCE                                                                     COMPOUNDS                                                                     verapamil   26                                                                cyclosporin A                                                                            285                                                                COMPOUNDS                                                                     OF THE                                                                        EXAMPLES                                                                       5         572                                                                 9         192                                                                12         450                                                                13         458                                                                19         309                                                                21         330                                                                23         339                                                                25         521                                                                28         464                                                                ______________________________________                                    

ACTIVITY IN VIVO

                  TABLE 3                                                         ______________________________________                                        Increase in the anti-tumour activity of                                       VCR caused by the compounds of the present                                    invention, administered i.p., on the line P388/VCR                            COMPOUNDS TESTED                                                                             DOSE (mg/kg) i.p.                                                                           T/C %   T/V                                      ______________________________________                                        No compound (VCR only)                                                                       --            140     1                                        Example 1      25            215     1.54                                                    50            239     1.71                                                    75            176     1.26                                     Example 2      25            192     1.37                                                    50            224     1.60                                                    75            235     1.68                                     ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Increase in the anti-tumour activity of                                       VCR caused by the compounds of the present                                    invention, administered p.o., on the line P388/VCR                            COMPOUNDS TESTED                                                                             DOSE (mg/kg) p.o.                                                                            T/C    T/V                                      ______________________________________                                        No compound (VCR only)                                                                       --            121     1                                        Compounds of the                                                              Examples                                                                      1              100           209     1.73                                     2              "             172     1.42                                     3              "             203     1.68                                     5              "             196     1.62                                     6              "             188     1.55                                     9              "             161     1.33                                     12             "             192     1.59                                     14             "             202     1.67                                     15             "             157     1.30                                     ______________________________________                                    

We claim:
 1. Bicyclic pyrimidine compounds selected from those offormula I: ##STR16## wherein: T and U, which are the same or different,each represents a --CH-- radical or a nitrogen atom so as to form withthe pyrimidinyl group a heterocycle selected from: purine,pyrazolo[3,4-d]pyrimidine, and 1,2,3-triazolo[4,5-d]pyrimidine;R and R',which are the same or different, each represents an alkyl radical having1 to 5 carbon atoms inclusive or an alkenyl radical having 2 to 5 carbonatoms inclusive, each in straight or branched chain; A represents aheteromonocyclic radical of formula: ##STR17## wherein: B represents aradical of formula: ##STR18## wherein R" is a hydrogen atom or an alkylradical having 1 to 5 carbon atoms inclusive in straight or branchedchain and t represents an integer of 1 to 3; inclusive p is zero or one;X and Y, which are the same or different, each represents a hydrogenatom, a halogen atom, or an alkyl or alkoxy radical each having 1 to 5carbon atoms inclusive in straight or branched chain; m and n, which arethe same or different, each represents an integer of 1 to 3 inclusive;R₁ and R₂, which are the same or different, each represents a hydrogenatom or an alkyl radical having 1 to 5 carbon atoms inclusive instraight or branched chain, or together represent a single bond, anoxygen or sulphur atom, a radical --(CH₂)_(r) -- in which r representsan integer of 1 to 3inclusive, a radical --CH═CH--, --O--CH₂ --,--S--CH₂ --, --SO₂ --CH₂ --, or --CO-CH₂ --, R₃ represents a hydrogenatom or a phenyl radical; and the chiral compounds and theirenantiomers, and their physiologically tolerable salts with appropriateacids.
 2. A compound of claim 1, which is9-allyl-6-allylamino-2-{4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]piperidino}purine.3. A compound of claim 1, which is9-allyl-6-allylamino-2-{4-[2,2-bis(4-fluorophenyl)ethylamino]piperidino}purine.4. A compound of claim 1, which is selected from9-allyl-6-allylamino-2-{4-[(6,11-dihydrodibenzo[b,e]oxepin-ll-yl)methylamino]piperidino}purineand its corresponding fumarate.
 5. A compound of claim 1, which isselected from9-allyl-6-allylamino-2-{4-[(5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]piperidino}purineand its corresponding fumarate.
 6. A compound of claim 1, which isselected from1-allyl-4-allylamino-6-{4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-methylamino]piperidino}pyrazolo[3,4-d]pyrimidineand its corresponding fumarate.
 7. A compound of claim 1, which is9-allyl-6-allylamino-2-{4-[(2,2-diphenylethyl)amino]piperidino}purine.8. A compound of claim 1, which is selected from9-allyl-6-allylamino-2-{4-[(2-methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]piperidino}purineand its corresponding fumarate.
 9. A compound of claim 1 which isselected from9-allyl-2-{4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]piperidino}-6-propylaminopurineand its corresponding fumarate.
 10. A compound of claim 1 which isselected from those of the formula I': ##STR19## wherein: --T and U,which are different, each represents --CH-- or nitrogen so as to formwith the pyrimidinyl group a heterocycle selected from purine andpyrazolo [3,4-d]pyrimidine,--R represents: --CH₂ --CH=CH₂ or --CH₂ --CH₂-CH₃ --R' is --CH₂ --CH=CH₂ substituted on a ring nitrogen atom --Arepresents: ##STR20## --p is 1 --X_(m) and Y_(n) are H --R_(s) is H--and R₁ R₂ together represent: --CH₂ --CH₂.
 11. A pharmaceuticalcomposition useful to suppress the resistance of tumour cells toanti-cancer agents, comprising as active ingredient a compound of claim1 together with an effective amount of one or more appropriatepharmaceutical excipients.
 12. A method of treating a "mammal" thecondition of which necessitates the suppression of the MDR type ofresistance of tumour cells to anti-cancer agents, which comprisesadministering to the said mammal an effective dose of a of claim 1required to effect the said suppression in the mammal concerned.